Aliskiren for heart failure: a systematic review and meta-analysis of randomized controlled trials

Abstract

ObjectiveTo systematically review and synthesize the currently available evidence of aliskiren for the treatment of heart failure.Materials and MethodsWe systematically searched the Cochrane, Embase and PubMed databases to identify the randomized controlled trials (RCT) on the effects of aliskiren on heart failure. Data were synthesized with random effects model and presented in forest plot. Publication bias was evaluated with funnel plot. Heterogeneity was evaluated with Begg's test and Egger's test.ResultsOf 124 studies, 6 RCT of 9845 heart failure patients were included for meta-analysis, including 3727 patients receiving aliskiren. Compared with the controls, aliskiren did not significantly reduce the all-cause mortality (1.02 [0.91–1.14], I2 = 0%) or cardiovascular mortality (1.02 [0.88–1.17], I2 = 7.3%) of heart failure patients. Total adverse events, renal dysfunction, hypotension and hyperkalaemia were not significantly different between the aliskiren group and control group. Begg's test and Egger's test indicated low heterogeneity. Funnel plots indicated low publication bias.ConclusionsAliskiren, either used alone or combined with standard medical therapy, does not significantly reduce the all-cause mortality or cardiovascular mortality of heart failure patients. Although aliskiren does not cause statistically higher adverse events, its adverse events may not be neglected.

Normalizing Plasma Renin Activity in Experimental Dilated Cardiomyopathy: Effects on Edema, Cachexia, and Survival

“…We examined the pathophysiologic contribution of elevated plasma renin activity concentrations to the progression of HFrEF as assessed by the development of edema, cachexia/sarcopenia, and mortality, in a randomized and blinded study. In contrast to previous trials, we intentionally chose an oral dose (100 mg/kg) of the DRI-aliskiren to selectively normalize pathological levels of plasma renin activity, rather than the larger doses, which may affect other pathways [38,39]. We show that targeted suppression with DRI-aliskiren, initiated at Stage B HF, reduces elevated plasma renin activity concentration to normal levels and decreased plasma neprilysin levels, without affecting the plasma levels of Ang II and aldosterone.…”

Current and emerging drug targets in heart failure treatment

“…Although a potential advantage from a double RAAS blockade with a combination of ACE inhibitors and ARBs may be envisaged, such strategy did not prove effective in clinical practice. Further, the direct renin inhibitor aliskiren did not reduce the rates of all-cause and cardiovascular mortality in HF patients [36]. Novel renin inhibitors are currently under investigation and are showing promising results in murine models [37].…”

Renin Activity in Heart Failure with Reduced Systolic Function—New Insights

“…Soon thereafter, this small-molecule inhibitor was enrolled in several clinical trials [40,41,217,218,219] to investigate the clinical effect of the drug against and in combination with standard therapeutic medications for the treatment of HF. The clinical trials were largely neutral [40,41,42,218,219,220], with most reporting no reduction in cardiovascular deaths or rehospitalizations due to DRI or the combination of RAAS blockers (ACE-I, beta-blockers, etc.). Some trials even stopped prematurely due to increases in adverse events compared to control groups.…”

“…Although the majority of DRI studies have focused on patients with rEF for enrollment criteria [41,42,217,218,219,228], newer trials are starting to consider targeting renin activity in patients with preserved EF [233]. Additionally, the systemic nature, growing comorbidities and classification of HF need to be considered when attempting to modulate RAAS/NP in HF [38,39,234,235,236,237].…”

“…Direct renin inhibitors (DRI) are designed to block enzymatically active renin from triggering a pathological alteration of downstream pathways. However, clinical trials have failed to demonstrate the value of renin activity inhibition for improving outcomes for patients with HF on concurrent RAAS blockers or diuretics [40,41,42]. Complicating the issue is the heterogeneity of patient plasma renin activity levels and their individualized responses to plasma renin activity levels on the background of RAAS blockers or HF progression itself.…”